The following discussion of the background of the disclosure is merely provided to aid the reader in understanding the binding partners, compositions, methods and uses described in this document, and is not admitted to describe or constitute prior art.
Protective immunity against certain diseases is dependent on the differential induction of specific pro-inflammatory T-cell (T lymphocyte) populations by antigen presenting cells (APCs) of the innate immune system, such as dendritic cells (DCs) and macrophages. Two such T-cell populations, responsible for mediating cellular immunity to a wide range of pathogens, are Th1 and Th17 cells. Both Th1 and more recently Th17 T cell populations have been implicated as mediators of autoimmune and chronic inflammatory diseases, and thus serve as relevant cellular targets for immunosuppressive agents. Furthermore, Dendritic Cells, as initiators of T-cell responses, are a second cellular target for therapies designed to combat inflammatory disease. Multiple Sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system (CNS), characterized by inflammatory infiltrates of T-cells, B cells, macrophages and focal demyelinating plaques within the CNS. Both Th1 and Th17 cell-mediated responses have been shown to play a role in the development of inflammatory demyelination. Myelin-reactive T-cells from MS patients produce cytokines consistent with a Th1-mediated response, while microarray studies of MS lesions from patients demonstrate increased expression of IL-23R.
A relevant model for studying the mechanisms of autoimmune inflammatory responses, and in particular MS, is the experimental autoimmune encephalomyelitis (EAE) animal model of inflammatory demyelinating disease that shares clinical and neuropathological changes with multiple sclerosis (MS). It has been accepted for many years that EAE is largely a CD4+Th1-mediated disease, though a pathogenic role for CD8+ T-cells in the induction of EAE has also been demonstrated. More recently however, it has been demonstrated that an IL-17 producing T cell subset plays a critical role in the pathogenesis of EAE. While there is still some debate in the literature, it is likely that Th1 and Th17 cells cooperate to induce the development of organ-specific autoimmunity.
CD6 is an important cell surface protein predominantly expressed by human T cells and a subset of B cells, as well as by some B cell chronic lymphocytic leukemias and neurons [Aruffo et al., J. Exp. Med. 1991, 174:949; Kantoun et al., J. Immunol. 1981, 127:987; Mayer et al., J. Neuroimmunol. 1990. 29:193]. CD6 is a member of a large family of proteins characterized by having at least one domain homologous to the scavenger receptor cysteine-rich domain (SRCR) of type I macrophages [Matsumoto, et al., J. Exp. Med. 1991, 173:55 and Resnick et al., Trends Biochem. Sci. 1994, 19:5]. Other members of this family include CD5 [Jones et al., Nature. 1986, 323:346]; cyclophilin C [Friedman et al. 1993, PNAS 90:6815]; complement factor I, which binds activated complement proteins C3b and C4b [Goldberger, et al., J. Biol. Chem. 1987, 262:10065]; bovine WC-1 expressed by .tau./.delta. T cells [Wijingaard et al., J. Immunol. 1992, 149:3273] and M130 [Law et al., Eur J. Immunol. 1993, 23:2320], a macrophage activation marker.
Blocking studies using anti-CD6 monoclonal antibodies (mAbs) suggest that CD6 plays an important role in T cell development by regulating T cell adhesive interactions with thymic epithelial (TE) cells (Patel et al., J. Exp. Med. (1995) 181:1563-1568). Additional studies have shown that CD6 can function as an important accessory molecule in T cell activation. For example, certain anti-CD6 mAb are directly mitogenic for T cells (Gangemi et al., J. Immunol. (1989) 143:2439; Bott et al., Int. Immunol. (1993) 7:783), whereas others are able to co-stimulate T cell proliferation in conjunction with anti-CD3, anti-CD2 or PMA (Gangemi et al., J. Immunol. (1989) 143:2439; Morimoto et al., J. Immunol. (1988) 140:2165-2170; Osorio et al., Cell. Immunol. (1994) 154:23). Yet additional evidence of the role of CD6 in T cell activation comes from studies showing that CD6 becomes hyperphosphorylated on Ser and Thr residues (Swack et al., Mol. Immunol. (1989) 26:1037-1049; Swack et al., J. Biol. Chem. (1991) 266:7137; Cardenas et al., J. Immunol., 145:1450-1455 (1990)) and phosphorylated on Tyr residues (Wee et al., J. Exp. Med. (1993) 177:219-223) following T cell activation. These and other studies implicate CD6 as an important modulator of both immature and mature T cell function in vivo, affecting both T cell activation and signal transduction (De Wit, J., et al., Blood (2011) 118:6107-6114).